title: A novel kindling model of temporal lobe epilepsy in rhesus monkeys induced by Coriaria lactone.
abstract: One of the major challenges in developing novel therapeutics for human epileptic disorders derives from the limitation of knowledge of the processes by which epilepsy is generated (epileptogenesis). Furthermore, the inability to obtain human samples at the early stage of epilepsy hinders studies designed to further understand epileptogenesis. Thus, an effective animal model is critical for studies investigating this process. The purpose of this study was to establish a new primate kindling model of temporal lobe epilepsy (TLE) as an animal model of epileptogenesis. Here, repeated injections of Coriaria lactone (CL) at a subthreshold dose elicited partial seizures that culminated in secondarily generalized tonic-clonic seizures. The sequence of events and features of the behaviors observed in this model simulated those observed in human TLE. Electroencephalogram monitoring revealed the temporal lobe origins of the epileptiform potentials, which were consistent with the behavioral changes observed. A total of 7 rhesus monkeys (78%) were kindled with a median of 48 (41 to 60) CL injections. Both the seizure-induction and mortality rates were dose-dependent. A CL injection at 1.50mg/kg showed the lowest animal mortality rate (0%) and the highest seizure-induction rate (100%). Extensive kindling by CL injections with a median of 97 injections (overkindling) subsequently resulted in the recurrence of spontaneous seizures in rhesus monkeys with frequency patterns that were similar to those observed in human TLE. In addition, rhesus monkeys subjected to large numbers of kindling stimuli displayed mitochondrial damage and astrocyte activation in a pattern that was similar to the neuropathological changes characteristic of human TLE. Thus, a kindling TLE model in rhesus monkeys representing a primate animal model of epileptogenesis was established for the first time using repeated intramuscular injections of Coriaria lactone. This model was easily and efficiently performed and resulted in behavioral, electrographical, and anatomical characteristics of human TLE. Thus, this model might be used in future investigations of the mechanisms involved in the epileptogenesis of TLE and in the development of new antiepileptic drugs.
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
authors.forename: Tian-Hua
authors.initials: TH
authors.lastname: Yang
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Tang
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007696:Kindling, Neurologic / Q000187:drug effects*; D007783:Lactones / Q000009:adverse effects*; D008253:Macaca mulatta; D008297:Male; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007783:Lactones; C049836:coriaria lactone
keywords: Animal model; CL; Coriaria lactone; Epilepsy; HE; Hematoxylin–eosin; Kindling; Primate; TLE; Temporal lobe epilepsy